Control of autoimmunity and allograft rejection by manipulation of endogenous regulatory mechanisms has long been a prized objective of physicians and scientists. We believe that recent insights into the role of epigenetics in the regulation of gene expression and cell function suggest new therapeutic opportunities that might contribute significantly to achieving that objective. A major outcome of this ongoing epigenetic research has been recognition of the potential for pharmacologic regulation of chromatin remodeling and gene transcription by the inhibition of histone/protein deacetylases (HDACs) and DNA methyltransferases (DNMTs). While pan-HDAC inhibitors are mainly being developed for oncology application, their use in inflammatory conditions, while being considered, is probably unlikely to be pursued, given their broad actions and considerable toxicities. A few HDAC isoform-selective compounds are also known, especially those that are HDAC6-selective inhibitors. A major function of HDAC6 is to regulate the intracellular handling and disposal of polyubiquitinated proteins. As a result, HDAC6 isoform selection inhibitors are available and are being developed for clinical application in neurodegenerative diseases ("polyglutaminopathies") and for multiple myeloma. By contrast, we have focused on how HDAC6, which unlike other HDACs, exists primarily in the cytoplasm, and controls multiple inflammatory pathways, including the heat shock protein (HSP) pathway. Based upon our preliminary work, we believe that the application of HDAC6-selective inhibitors offers a truly innovative approach to control autoimmunity and prevent organ transplant rejection. We propose to investigate the anti-inflammatory effects of HDAC6 and/or associated HSP90 targeting to determine which is best suited for further therapeutic development in inflammation. Our plan is to pursue the following aims: Aim 1) Establish the therapeutic effects of HDAC6 targeting in models of autoimmunity and transplant rejection. Aim 2) Determine whether HSP90 targeting has important therapeutic effects on the development of autoimmunity and transplant rejection. Aim 3) Assess whether the effects of HDAC6 targeting in autoimmunity and transplant rejection are primarily mediated through modulation of the HSP90 pathway or whether additional HSP90-independent effects of HDAC6 targeting are centrally involved. Our studies should have major consequences for the development of new strategies for therapy in patients with multiple types of autoimmunity and transplant rejection.